A considerable effort has been devoted to the synthesis and study of porphyrins and other tetrapyrrolic macrocycles, much less is known about the larger aromatic pyrrole-containing systems, the so-called "expanded porphyrins." Such systems, by virtue of containing a greater number of .pi. electrons, additional coordinating heteroatoms and a larger central binding core, may offer advantages over the porphyrins.
The pursuit of these compounds began several decades ago with the first reported synthesis of sapphyrin from tripyrrane dicarboxylic acid and bipyrroledicarboxaldehyde. (Woodward, R. B., Aromaticity Conference, Scheffield, England, 1966; see also, Broadhurst et al., J. Chem. Soc. Perkins Trans. (1972) 1:2111 and Bauer et al. (1983) J. Am. Chem. Soc. 105:6429). The synthesis of smaragdyrin from bipyrroledicarboxaldehyde and pyrroledipyrromethane dicarboxylic acid was reported in 1970 by M. M. King. (Ph.D. Dissertation, Harvard University, Cambridge, Mass.)
The uranyl complex of superphthalocyanine is another pentapyrrolic macrocyclic compound of historical importance. This compound was prepared by direct template condensation of dicyanobenzene with uranyl dichloride, however, the free base is unstable (Day et al. (1975) J. Am. Chem. Soc. 97:4519). Demetalation resulted in contraction of the ring to form phthalocyanine (Marks, T. J. and D. R. Stojakovic (1978) J. Am. Chem. Soc. 100:1695).
Gossauer synthesized the first hexaphyrin by condensing a bis-.alpha.-tripyrrane with a tripyrrane dialdehyde, followed by oxidation (Bull. Soc. Chim. Belg. (1983) 92:793). Of the six methine bridges present in the hexaphyrin, two have E configuration (Id.). Charriere reported that hexaphyrin forms bimetallic complexes with several transition metals (1987, Thesis, University de Fribourg, Suisse). Another hexapyrrolic system, rubyrin, has been recently synthesized and structurally characterized (Sessler et al. (1991a) Angew. Chem. Int. Ed. Engl. 30:977).
Vinylogous porphyrins or platyrins are another important class of pyrrole-containing macrocycles first described by R. A. Berger and E. LeGoff (Tetra. Lett. (1978) 44:4225; see also, LeGoff, E. and O. G. Weaver (1987) J. Org. Chem. 52:711; and Franck et al. (1988) Proc. SPIE Int. Soc. Opt. Eng., Ser. 5, 997:107). These compounds are generally synthesized by reacting a dipyrromethane with a vinylaldehyde-substituted dipyrromethane (Beckman et al. (1990) Angew. Chem. Int. Ed. Engl. 29:1395). Bisvinylogous expanded porphyrins were further expanded to tetravinylogous porphyrins in which all four of the normally one atom meso bridges are enlarged. Tetravinylogous porphyrins are made by an acid-catalyzed self-condensation of the N-protected, pyrrole-substituted allyl alcohol. Tetravinylogous porphyrins have a very intense Soret-like band shift of more than 150 nm from that of the normal porphyrins (Gosmann, M. and B. Franck (1986) Angew. Chem. Int. Ed. Engl. 25:1100; Knubel, G. and B. Franck (1988) Angew. Chem. Int. Ed. Engl. 27:1170). In addition, the synthesis of bisvinylogous porphycene has recently been reported (Jux et al. (1990) Angew. Chem. Int. Ed. Engl. 29:1385; Vogel et al. (1990) Angew. Chem. Int. Ed. Engl. 29:1387).
Schiff-base compounds represented by texaphyrin are another class of pyrrole containing macrocyles (Sessler et al. (1987) J. Org. Chem. 52:4394; Sessler et al. (1988) J. Am. Chem. Soc. 110:5586). Texaphyrin is synthesized by acid-catalyzed condensation of tripyrrane dialdehyde with o-phenylenediamine. Several analogs of texaphyrin have been prepared using similar strategies (Sessler et al. (1991b) Abstract of the 201st Natl. Soc. Mtg., Inorganic Division; Sessler et al. (1992) Inorg. Chem. 28:529).
The use of porphyrins, combined with irradiation, for the detection and treatment of malignant cells has, by this time, some considerable history. (See, e.g., PORPHYRIN PHOTOSENSITIZATION (Kessel, D. et al., eds. Plenum Press, 1983). Certain porphyrins seem "naturally" capable of localizing malignant cells. When irradiated, porphyrins have two properties which make them useful. First, when irradiated with ultraviolet or visible light, they may fluorescence, and thus be useful in diagnostic methods related to detection of malignancy (see, for example, Kessel et al., supra; Gregory, H. B. Jr. et al., Ann. Surg. (1968) 167:827-829).
In addition, when irradiated with ultraviolet (UV), visible, or near-infrared light, certain porphyrins exhibit a cytotoxic effect on the cells in which they are localized (see, for example, Diamond, I. et al., Lancet (1972) 2:1175-1177; Dougherty, T. J. et al., Cancer Research (1978) 38:2628-2635; Dougherty, T. J. et al., THE SCIENCE OF PHOTO MEDICINE 625-638 (J. D. Regan & J. A. Parrish, eds., 1982); Dougherty, T. J. et al., CANCER: PRINCIPLES AND PRACTICE OF ONCOLOGY 1836-1844 (V. T. DeVita Jr. et al., eds., 1982). Certain of the expanded porphyrins such as sapphyrin, texaphyrin and vinylogous porphyrins possess unique long-wavelength and singlet oxygen producing properties which make them attractive as potential photosensitizers for use in tumor phototherapy (Maiya et al. (1990) J. Phys. Chem. 94:3597; Sessler et al. (1991c) SPIE Soc. 1426:318; Franck et al., supra).
While the conjugation of certain porphyrins, such as hematoporphyrin, to immunoglobulins specific for targeted cells may refine the ability of certain porphyrins to home to the desired cells or tissue, this still does not solve another problem ancillary to this general therapeutic approach, namely that the wavelength for irradiation required to activate certain porphyrins, which is in the range of 630 nanometers, is also an energy which is readily absorbed by other porphyrins and natural chromophores normally present in the blood and other tissues. Therefore, the depth of the effective treatment has been limited to a few millimeters because of blocking effects of light-absorbing natural chromophores such as hemoglobin. Accordingly, it would be desirable to administer compounds to mediate the effects of irradiation which can be excited at longer wavelengths thus avoiding the blocking effects of natural chromophores present throughout the subject organism.
In addition to phototherapy, expanded porphyrins are useful in magnetic resonance imaging (MRI). MRI is a noninvasive, non-ionizing method that allows normal and abnormal tissue to be observed and recognized at the early stages of development. At this time MRI has a significant drawback, however, in that the degree of signal enhancement for diseased versus normal tissues is often insufficient to allow this method to be used in many clinical situations. To overcome this problem, considerable effort is underway to develop contrast reagents for MRI. Paramagnetic metal complexes, such as those derived from gadolinium(III) (Gd) have recently proven particularly efficient in clinical trials.
To date, the coordination of gadolinium in MRI contrast agents has been achieved using carboxylate-type ligands. (See, for example, Lauffer, R. B. (1987) Chem. Rev. 87:901; Kornguth et al. (1987) J. Neursurg. 66:898; Koenig et al. (1986) Invest. Radiol. 21:697; Chacheris et al. (1987) Inorg. Chem. 26:958; Loncin et al. (1986) Inorg. Chem. 25:2646; Chang, C. A. and V. C. Sekhar (1987) Inorg. Chem. 26:1981). The known systems are all of high thermodynamic stability but high intrinsic lability. Certain expanded porphyrins, on the other hand, can form stable complexes with Gd(III) which does not form stable complexes with normal porphyrins. As a result, they provide an improved approach as MRI contrast agents. Sessler et al. reported that texaphyrin forms an extremely stable Gd(III) complex in vitro (Sessler et al. (1989) Inorg. Chem. 28:3390). In addition to Gd(III), texaphyrin has been reported to form complexes with a variety of transition metals such as Cd and Eu (Sessler, J. L. and A. K. Burrell (1992) Top. Cur. Chem. 161:177).